High normal blood pressure in increasingly recognized as an important cardiovascular risk factor in part due to the likelihood of progression to hypertension. However, there is considerable heterogeneity in the risk of hypertension; some individuals progress while others maintain or regress. Thus, clinicians are unable to identify those at highest risk. Further, the effect of treatment of high normal blood pressure (BP) on the progression to hypertension is unknown. Consequently, my colleagues and I designed the Trial of Preventing Hypertension (TROPHY) as a prospective randomized placebo controlled trial of short-term monotherapy with the angiotensin receptor blocker (ARB) candesartan cilexitil in 809 subjects with high normal BP. Trophy provides a unique opportunity to study the mechanisms of the progression to hypertension. Emerging basic research emphasizes the role of superoxide (.O2-) as a major mechanism by which chronic exposure to low concentrations of angiotensin II (All) includes progressive hypertension. Via interaction with All receptors in the vessel wall, All activates NAD(P)H oxidases producing .O2- and other reactive oxygen species that a) quench nitric oxide (NO), leading to NO deficient hypertension and b) stimulate signaling of vascular smooth muscle cell growth. TROPHY provides a new opportunity to translate this basic research from animal models to the clinical setting. Major Mechanistic Hypothesis: All receptor mediated generation of .O2- both quenches NO and stimulates vascular hypertrophy, and thereby constitutes the major mechanism of progression to hypertension from high normal BP. Specific Aims: Utilizing the TROPHY trial of 800 subjects on placebo or short-term ARB treatment we will: 1) in the placebo group, determine if individuals with high normal BP and high oxidative stress levels (F2 isoprostanes and glutathione ratio) are at high risk for progression to hypertension; 2) in the ARB group, determine if short-term treatment lowers oxidative stress levels compared to placebo and if the level of oxidative stress predicts failure to progress to hypertension; and 3) determine genetic sequence variants in the All, oxidative stress, and NO pathways associated with progression to hypertension or failure to progress to hypertension.